Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/4035—Isoindoles, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

• the present invention provides a new amorphous form of apremilast, pharmaceutical compositions comprising same, methods for preparation and use thereof in treating conditions mediated by inhibition of TNF-ot production or inhibition of phosphodiesterase 4 (PDE4), e.g., psoriatic arthritis and other chronic inflammatory diseases.
• PDE4 phosphodiesterase 4
• Apremilast is a selective inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP).
• PDE4 phosphodiesterase 4
• the inhibition of PDE4 results in increased intracellular cAMP levels.
• Apremilast is chemically named N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide, and is represented by the following chemical structure:
• Apremilast is approved in the United States for treatment of adults with active psoriatic arthritis. It is also being tested for treating other chronic inflammatory diseases such as psoriasis, ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis. The specific mechanism(s) responsible to the apremilast' s therapeutic action in psoriatic arthritis patients is not well defined.
• US 6,020,358 discloses substituted phenethylsulfones, including apremilast, and methods of use thereof for reducing TNFot levels.
• WO 2003/080048 and WO 2003/080049 disclose the use of the (-) and (+) enantiomers of apremilast, respectively, in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.
• WO 2009/120167 discloses seven solid forms of the (+) enantiomer of apremilast, designated as Forms A to G, including methods of preparation.
• the crystalline form A is characterized by diffraction peaks in the X-ray powder diffraction pattern at 8.1 °, 15.2°, 17.4°, 23.6° and 25.1° degrees 2 ⁇ .
• the crystalline form B is characterized by diffraction peaks in the X-ray powder diffraction pattern at 10.1 °, 13.5°, 20.7° and 26.9° degrees 2 ⁇ .
• the crystalline form C is characterized by peaks in the X-ray powder diffraction pattern at 7.5°, 11.3°, 16.4°, 17.8° and 26.4° degrees 2 ⁇ .
• the crystalline form D is characterized by diffraction peaks in the X-ray powder diffraction pattern at 7.5°, 11.3°, 16.3°, 25.2° and 26.0° degrees 2 ⁇ .
• the crystalline form E is characterized by peaks in the X-ray powder diffraction pattern at 7.6°, 9.2°, 11.4°, 17.9° and 26.6° degrees 2 ⁇ .
• the crystalline form F is characterized by diffraction peaks in the X-ray powder diffraction pattern at 8.1 °, 8.6°, 15.6°, 17.3° and 25.4° degrees 2 ⁇ .
• the crystalline form G is characterized by diffraction peaks in the X-ray powder diffraction pattern at 7.9°, 11.7°, 16.8°, 18.1 ° and 26.7° degrees 2 ⁇ .
• WO 2009/120167 also generally mentions an amorphous form of apremilast but does not teach that a single amorphous form was actually obtained or characterized.
• a new crystalline or amorphous form of a compound may possess physical properties that differs from, and is advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compatibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use. There remains an unmet need for additional solid state forms of apremilast having good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.
• the present invention provides a new amorphous form of apremilast, pharmaceutical compositions comprising same, methods for its preparation and use thereof in treating conditions mediated by reduction in the levels of TNF-ot or inhibition of PDE4, in particular, psoriatic arthritis and other chronic inflammatory diseases.
• the present invention is based in part on the unexpected finding that the new amorphous form disclosed herein possesses advantageous physical and/or chemical properties which render its manufacturing, processing, formulation and storage as medicament beneficial.
• This form has a good bioavailability as well as desirable stability characteristics which enable its incorporation into a variety of different formulations that are particularly suitable for pharmaceutical utility.
• the present invention also provides processes for preparing amorphous apremilast, as described herein.
• the invention further provides an amorphous apremilast prepared by such processes.
• the present invention provides a process for preparing an amorphous apremilast, comprising the steps of:
• step (b) cooling the melted apremilast obtained in step (a), so as to provide amorphous apremilast.
• the cooling in step (b) is selected from fast cooling and slow cooling.
• fast cooling and slow cooling are selected from fast cooling and slow cooling.
• the invention further provides an amorphous apremilast prepared by the above- described process.
• the present invention provides a process for preparing an amorphous apremilast, the process comprising the steps of: (a) dissolving apremilast in a solvent or a mixture of solvents selected from THF, acetone and DMF:EtOH; and
• the DMF:EtOH is used at a volume ratio of about
• the invention further provides an amorphous apremilast prepared by the above-described process.
• the present invention provides a process for preparing an amorphous apremilast, the process comprising the steps of:
• the apremilast solution is added to the anti-solvent.
• the anti-solvent is added to the apremilast solution.
• the volume ratio of solvent to anti-solvent is about 1 to about 10.
• the solvent/anti-solvent mixture is heptane and acetone, wherein heptane is added to acetone.
• the solvent/anti-solvent mixture is heptane and acetone, wherein acetone is added to heptane.
• the solvent/anti-solvent mixture is heptane and MEK, preferably wherein the heptane is added to MEK.
• the solvent/anti-solvent mixture is THF and heptane, preferably wherein the THF is added to heptane.
• the solvent/anti-solvent mixture is water and acetone, preferably wherein the water is added to acetone.
• the process for preparing an amorphous apremilast further comprises the step of drying the apremilast obtained in step (b) under vacuum at a temperature of about 25°C.
• the invention further provides an amorphous apremilast prepared by the above- described process.
• the present invention provides a process for preparing an amorphous apremilast, the process comprising the steps of:
• step (b) cooling the apremilast obtained in step (a) to about 25°C, so as to provide amorphous apremilast.
• the invention further provides an amorphous apremilast prepared by the above- described process.
• the present invention provides an amorphous form of apremilast.
• the amorphous apremilast is characterized by an X-ray diffraction (XRD) profile substantially as shown in any of the Figures 1, 4, 7, 10, 13, 20, 23, 27, 28, 29 or 30.
• XRD X-ray diffraction
• the present invention provides amorphous form of apremilast characterized by a modulated DSC (mDSC) profile substantially as shown in any of the Figures 2, 5, 8, 11A, 11B, 14, 16, 18, 21, 24, 31 , 32, 33, 34 or 35, or a DSC profile substantially as shown in Figure 36.
• mDSC modulated DSC
• the amorphous apremilast has a glass transition temperature between about 36°C and about 79°C, for example about 36.1°C, 38.0°C, 41.9°C, 44.1°C, 48.2°C, 60.9°C, 75.9°C, 77.2°C, 77.7°C, 78.2°C, or about 133.6°C.
• the amorphous apremilast is characterized by a TGA profile substantially as shown in any of the Figures 3, 6, 9, 12, 15, 17, 19, 22 or 25. Each possibility represents a separate embodiment of the present invention.
• the amorphous apremilast of the present invention is further characterized by a Dynamic Vapor Sorption (DVS) profile substantially as shown in Figures 26 A and 26B.
• DVD Dynamic Vapor Sorption
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising as an active ingredient the amorphous apremilast as described herein, and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is in the form of a tablet.
• the amorphous apremilast of the present invention is useful for treating a medical condition mediated TNFa or by PDE4.
• the present invention provides a method of treating a medical condition mediated by TNFa or by PDE4 comprising administering to a subject in need thereof an effective amount of the amorphous apremilast of the present invention, or a pharmaceutical composition comprising said amorphous apremilast.
• the present invention provides the use of the amorphous apremilast of the present invention for treating medical conditions mediated by TNFa or PDE4.
• the medical condition is selected from the group consisting of psoriasis, psoriatic arthritis, ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis.
• the subject in need is mammal, preferably a human.
• the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter.
• the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
• Figure 1 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by method I (in THF).
• Figure 2 illustrates a characteristic modulated Differential Scanning Calorimetry
• FIG 3 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method I (in THF).
• Figure 4 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by method I (in acetone).
• TGA Thermogravimetric analysis
• Figure 5 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by method I (in acetone).
• mDSC Differential Scanning Calorimetry
• FIG. 6 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method I (in acetone).
• TGA Thermogravimetric analysis
• mDSC Differential Scanning Calorimetry
• TGA Thermogravimetric analysis
• Figure 10 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by method II (panel A-B; slow and fast cooling). Also shown for comparison is the X-ray diffraction pattern of crystalline apremilast designated as From B in WO 2009/120167(panel C).
• Figure 11 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by method II.
• Fig. 11A mDSC profile of an amorphous apremilast obtained by slow cooling.
• Fig. 11B mDSC profile of an amorphous apremilast obtained by fast cooling.
• Figure 12 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method II (slow cooling).
• TGA Thermogravimetric analysis
• Figure 13 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by method III.
• Panels A-E represent the following solvent-anti-solvent systems: addition of (A) THF to heptane; (B) water to acetone; (C) heptane to MEK; (D) acetone to heptane; and (E) heptane to acetone.
• the X-ray diffraction pattern of crystalline apremilast designated as Form B in WO 2009/120167 (panel F).
• Figure 14 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by method III (addition of acetone to heptane).
• mDSC Differential Scanning Calorimetry
• Figure 15 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method III (addition of acetone to heptane).
• TGA Thermogravimetric analysis
• Figure 16 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by method III (addition of THF to heptane).
• mDSC Differential Scanning Calorimetry
• FIG 17 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method III (addition of THF to heptane).
• TGA Thermogravimetric analysis
• Figure 18 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by method III (addition of water to acetone).
• mDSC Differential Scanning Calorimetry
• Figure 19 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method III (addition of water to acetone).
• TGA Thermogravimetric analysis
• Figure 20 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by method IV (panel A). Also shown for comparison is the X-ray diffraction pattern of the crystalline apremilast designated as Form B of WO 2009/120167 (panel B).
• Figure 21 illustrates a characteristic modulated Differential Scanning Calorimetry
• Figure 22 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by method IV.
• Figure 23 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone; panel A). Also shown for comparison is the X-ray diffraction pattern of the amorphous form of apremilast obtained on a small scale by the same method (panel B).
• TGA Thermogravimetric analysis
• Figure 24 illustrates a characteristic modulated Differential Scanning Calorimetry
• Figure 25 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• TGA Thermogravimetric analysis
• Figure 26 illustrates a characteristic Dynamic Vapor Sorption (DVS) isotherm plot of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• Fig. 26A DVS isotherm plot. Sorption is represented by diamonds and desorption is represented by squares.
• Fig. 26B DVS change in mass (ref) plot.
• Figure 27 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 25°C in a closed glass vial.
• Figure 28 illustrates a characteristic X-ray diffraction pattern of an anamorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 25°C/60 RH.
• Figure 29 illustrates a characteristic X-ray diffraction pattern of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 40°C in a closed glass vial.
• Figure 30 illustrates a characteristic X-ray diffraction pattern of an up amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone). The apremilast was stored at 40°C/75 RH.
• Figure 31 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 25°C in a closed glass vial.
• Figure 32 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 25°C/60 RH.
• Figure 33 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 40°C in a closed glass vial.
• Figure 34 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 40°C/75 RH.
• Figure 35 illustrates a characteristic modulated Differential Scanning Calorimetry (mDSC) profile of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 40°C/75 RH.
• Figure 36 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile at a heating rate of 50°C/min of an amorphous form of apremilast obtained by scaled-up method III (addition of water to acetone).
• the apremilast was stored at 40°C/75 RH.
• Panels A-C represent the following time points (A) after two weeks; (B) after four weeks; and (C) after 3 months. Also shown for comparison is the DSC profile of the crystalline apremilast designated as Form B of WO 2009/120167 (panel D).
• the present invention is directed to a novel amorphous form of N-[2-[(lS)-l-(3- emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4- yl]acetamide (apremilast).
• the present invention further provides methods of preparing the novel amorphous form of the present invention, as well as an amorphous apremilast obtained by such processes.
• the present invention is further directed to pharmaceutical compositions comprising the amorphous form of the present invention and a pharmaceutically acceptable carrier and their use in treating and/or preventing disorders ameliorated by the inhibition of TNF-ot production or the inhibition of PDE4, e.g., active psoriatic arthritis as well as other chronic inflammatory diseases.
• Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangements and/or conformations of the molecules. Polymorphism is the ability of a substance to exist in several different amorphous forms. Different forms of amorphous pharmaceuticals with readily discernible physical and chemical characteristics and some marked differences in their pharmaceutical performance have been reported. Even though amorphous materials do not exhibit long-range periodic atomic ordering, different amorphous phases of the same chemical substance can exhibit significant structural differences in their short-range atomic arrangement. These differences may lead to different physical and chemical properties such as density, stability, processability, dissolution and even bioavailability. Polymorphism in pharmaceuticals is reviewed in Hancock et al.
• the present invention provides processes for the preparation of amorphous apremilast.
• the apremilast starting material used in such processes may be prepared in accordance with any method known in the art, including, for example, the methods described in WO 2009/120167, WO 2003/080049, WO 2003/080048, and US 6,020,358. The contents of each of which are hereby incorporated by reference in their entirety.
• the apremilast starting material is heated until a melt is obtained, preferably under vacuum followed by controlled precipitation by slow/fast cooling.
• the solvent is then removed by spontaneous evaporation.
• the apremilast starting material is dissolved in a suitable solvent at room temperature to form an apremilast solution, followed by combining said solution with a suitable anti-solvent to afford the precipitation of amorphous apremilast.
• the apremilast solution is added to the anti-solvent.
• the anti-solvent is added to the apremilast solution.
• the anti-solvent is generally used in about a 10 fold excess relative to the solvent.
• the amorphous apremilast may be further dried under vacuum at a temperature of about 25°C.
• Suitable solvent-anti-solvent pairs include, but are not limited to, acetone -heptane, heptane- MEK, THF-heptane and water-acetone.
• Preferred solvents for this method are selected from acetone, MEK and THF.
• Preferred anti-solvents for this method are selected from water and heptane. Each possibility represents a separate embodiment of the present invention.
• the apremilast starting material is heated to a temperature of about 120°C at 5°C/min followed by spontaneous cooling to a temperature of about 25°C to afford the precipitation of apremilast of the present invention.
• the invention further provides an amorphous apremilast prepared by each of the processes as described herein.
• the present invention provides amorphous form of apremilast which is characterized by an X-ray diffraction pattern having a single broad peak expressed between about 10 and about 30 degrees two theta [2 ⁇ °] as is shown in any of the Figures 1, 4, 7, 10, 13, 20, 23, 27, 28, 29 or 30. Each possibility represents a separate embodiment of the present invention.
• the amorphous apremilast is further characterized by glass transition temperature and by using various techniques including, but not limited to, thermal analysis (e.g. thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), modulated differential scanning calorimetry (mDSC) and dynamic vapor sorption (DVS)).
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• mDSC modulated differential scanning calorimetry
• DVDS dynamic vapor sorption
• the amorphous apremilast of the present invention is characterized by a modulated DSC profile substantially as shown in any of the Figures 2, 5, 8, 11A, 11B, 14, 16, 18, 21, 24, 31 , 32, 33, 34 or 35, or a DSC profile substantially as shown in Figure 36.
• a modulated DSC profile substantially as shown in any of the Figures 2, 5, 8, 11A, 11B, 14, 16, 18, 21, 24, 31 , 32, 33, 34 or 35
• a DSC profile substantially as shown in Figure 36 Each possibility represents a separate embodiment of the present invention.
• the amorphous apremilast of the present invention is further characterized by a TGA profile substantially as shown in any of the Figures 3, 6, 9, 12, 15, 17, 19, 22 or 25.
• the amorphous form has a glass transition temperature between about 36°C and about 79°C.
• the glass transition temperature of amorphous apremilast is about 36.1°C, 38.0°C, 41.9°C, 44.1°C, 48.2°C, 60.9°C, 75.9°C, 77.2°C, 77.7°C, 78.2°C, or about 133.6°C.
• the amorphous apremilast of the present invention is further characterized by a Dynamic Vapor Sorption (DVS) profile substantially as shown in Figures 26 A and 26B. Each possibility represents a separate embodiment of the present invention.
• DVDS Dynamic Vapor Sorption
• novel amorphous form of the present invention is useful for the treatment of medical conditions mediated by inhibition of PDE4 or inhibition of TNF-ot production.
• the present invention provides a method of treating medical conditions mediated by PDE4 or TNF-ot comprising administering to a subject in need thereof an effective amount of the amorphous form of apremilast as described herein.
• the amorphous form of apremilast is administered in a pharmaceutical composition.
• the subject in need is mammal, preferably a human.
• the present invention relates to the use of an amorphous form of apremilast as described herein, or a pharmaceutical composition comprising such amorphous apremilast, in the manufacture of a medicament for treating medical condition mediated by PDE4 or TNF-ot.
• the medical condition is selected from the group consisting of psoriasis, psoriatic arthritis, ankylosing spondylitis, Behcet's disease, and rheumatoid arthritis.
• PDE4 diseases mediated by PDE4
• conditions ameliorated by PDE4 inhibition include HIV, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic obstructive pulmonary diseases, chronic pulmonary inflammatory diseases, dermatitis, inflammatory skin disease, atopic dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft rejection including graft versus host disease, auto immune disease, rheumatoid spondylitis, arthritic conditions (such as rheumatoid arthritis and osteoarthritis), osteoporosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, erythema nodosum lepro
• TNF-ot Other non- limiting examples of medical condition mediated by TNF-ot (i.e., conditions ameliorated by inhibition of TNF-ot production) include psoriasis, psoriatic arthritis, rheumatoid arthritis, chronic cutaneous sarcoid, giant cell arteritis, Parkinson's Disease, prurigo nodularis, lichen planus, complex apthosis, Behcet's Disease, lupus, hepatitis, uveitis, Sjogren's Disease, depression, interstitial cystitis, vulvodynia, prostatitis, osteoarthritis, diffuse large B cell lymphoma, polymyositis dermatomyositis, inclusion body myositis, erosive osteoarthritis, interstitial cystitis, hepatitis, endometriosis, radiculopathy, and pyoderma gangrenosum, among others. Each possibility represents a separate embodiment
• a therapeutically effective amount refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject.
• the amorphous apremilast of the present invention is used for the preparation of a medicament.
• the present invention further provides the administration of the amorphous apremilast of the present invention in combination therapy with one or more other active ingredients, for example other non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs.
• the combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by a skilled artisan.
• the present invention thus provides pharmaceutical compositions comprising amorphous apremilast and a pharmaceutically acceptable carrier.
• the pharmaceuticals can be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual. Each possibility is a separate embodiment of the invention.
• the amorphous apremilast of the present invention is administered orally.
• the pharmaceutical compositions may be formulated as tablets (including e.g. film-coated tablets, sublingual tablets and orally disintegrating tablets), powders, granules, dragees, pellets, pills, capsules (including soft capsules) and the like. Each possibility is a separate embodiment of the invention.
• Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts.
• the pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, anti-oxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.
• Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide.
• Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid.
• Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, a-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substituted hydroxypropyl cellulose.
• Suitable disintegrants include e.g.
• cross-linked povidone any cross-linked l-ethenyl-2-pyrrolidinone homo-polymer including polyvinylpyrrolidone (PVP) and 1 -vinyl-2-pyrrolidinone homo-polymer
• PVP polyvinylpyrrolidone
• Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like.
• Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid.
• Suitable antioxidants include e.g. sulfites, ascorbic acid and ot-tocopherol.
• Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like.
• Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin.
• Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid.
• Suitable bubbling agents include e.g. sodium bicarbonate.
• Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.
• the tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like.
• the active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• the tablets and other solid dosage forms may be made by compression or molding, optionally with one or more excipients as is known in the art.
• molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
• TGA IR Thermal Gravimetric Analysis
• QGA Hiden Quantitive Gas Analysis
• Tube Voltage 40 kV; Current: 40 mA.
• Method I Amorphous samples (about 1 mg) were run a modulated DSC using Tzero aluminum pans heated from 0°C to 200°C at speed of 2°C/min, with modulation temperature amplitude 1.0°C and modulation 60 s.
• Method II The two-cycle heating mDSC was run using Tzero aluminum hermetic pans with pinhole with first cycle heated from 0°C to 160°C at speed of 2°C/min and the second cycle from 0°C to 260°C at speed of 2°C/min.
• Samples (about 1-3 mg) were placed in an open platinum pan and heated from room temperature to 250°C-300°C at a rate of 10°C/min.
• Samples (about 10 mg) were transferred into a DVS pan, the weight changes were recorded with respect to the atmospheric humidity at 25°C.
• Apremilast (Form I) was dissolved in a solvent at room temperature and filtered. Anti- solvent (10 fold volume) was quickly added and stirred into the apremilast solution or the apremilast solution was quickly added and stirred into anti-solvent (10 fold volume). Once the precipitant formed, it was centrifuged at 10,000 rpm for 2 minutes. In a scaled up procedure (using 5 g of apremilast), once the precipitant formed, the solid was filtered and then dried in a vacuum drier at 25°C.
• Apremilast Form II (equivalent to form D of WO2009/120167) was heated to 120°C at 5°C/min and kept for 5 min, then cooled spontaneously to room temperature.
• FIG. 1 shows a characteristic XRPD of the amorphous form obtained by this method using THF as the solvent.
• Figure 2 illustrates a characteristic modulated DSC.
• the glass transition temperature of the amorphous form obtained by this method is 38.0°C.
• Figure 3 illustrates a characteristic TGA profile with a weight loss of about 1.12% between about 25°C and about 98°C and a weight loss of about 4.64% between about 98°C and about 180°C.
• Figure 4 shows a characteristic XRPD of the amorphous form obtained by this method using acetone as a solvent.
• Figure 5 illustrates a characteristic modulated DSC profile. The glass transition temperature of the amorphous form obtained by this method is 44.1°C.
• Figure 6 illustrates a characteristic TGA profile with a weight loss of about 1.25% between about 25°C and about 101°C, and a weight loss of about 1.82% between about 101°C and about 210°C.
• Figure 8 illustrates a characteristic modulated DSC profile.
• the glass transition temperature of the amorphous form obtained by this method is 36.1 °C.
• Figure 9 illustrates a characteristic TGA profile with a weight loss of about 2.07% between about 25°C and about 103°C, and a weight loss of about 4.31 % between about 103°C and about 217°C.
• Figure 12 illustrates a characteristic TGA profile of amorphous apremilast obtained by the slow cooling method, with a weight loss of about 0.29% between about 24°C and about 180°C
• Example 4 Amorphous Apremilast (Method III)
• Figure 13 panel (D) shows characteristic XRPD of the amorphous form obtained by addition of acetone to heptane.
• Figure 14 illustrates a characteristic modulated DSC. The glass transition temperature of the amorphous form obtained by this method is 41.9°C.
• Figure 15 illustrates a characteristic TGA profile with a weight loss of about 1.67% between about 20°C and about 96°C and a weight loss of about 2.90% between about 96°C and about 200°C.
• Figure 13 panel (A) shows characteristic XRPD of the amorphous form obtained by addition of THF to heptane.
• Figure 16 illustrates a characteristic modulated DSC profile. The glass transition temperature of the amorphous form obtained by this method is 60.9°C, based on the first heating cycle.
• Figure 17 illustrates a characteristic TGA profile with a weight loss of about 2.47% between about 26.3°C and about 100°C, and a weight loss of about 0.87% between about 100°C and about 200°C.
• Figure 13 panel (B) shows characteristic XRPD of the amorphous form obtained by addition of water to acetone.
• Figure 18 illustrates a characteristic modulated DSC profile. The glass transition temperature of the amorphous form obtained by this method is 78.2°C, based on the first heating cycle.
• Figure 19 illustrates a characteristic TGA profile with a weight loss of about 0.84% between about 29.9°C and about 100 °C, and a weight loss of about 0.76% between about 100°C and about 200°C.
• Figure 13 panel (C) shows characteristic XRPD of the amorphous form obtained by addition of heptane to MEK.
• Figure 13 panel (E) shows characteristic XRPD of the amorphous form obtained by addition of heptane to acetone.
• Figure 20 shows a characteristic XRPD of amorphous apremilast obtained by this method. Also shown for comparison is the X-ray diffraction pattern of the crystalline apremilast Form I (panel B).
• Figure 21 illustrates a characteristic modulated DSC profile. The glass transition temperature is 48.2°C.
• Figure 22 shows a characteristic TGA profile with a weight loss of about 1.98% between about 26 °C and about 120 °C, and a weight loss of about 1.51% between about 120 °C and about 200 °C.
• Figure 23 Also shown in Figure 23 panel (B) for comparison, is the X-ray diffraction pattern profile of the amorphous form of apremilast obtained on a small scale by the same method as described in Example 4.
• Figure 24 illustrates a characteristic modulated DSC profile of amorphous apremilast prepared by this method.
• the glass transition temperature of the amorphous form obtained by this method is 77.7°C and 133.6°C.
• Figure 25 illustrates a characteristic TGA profile of the amorphous apremilast prepared by this method, with a weight loss of about 0.44% between about 25 °C and about 100 °C and a weight loss of about 0.16% between about 100 °C and about 200 °C.
• Figure 26 shows a characteristic DVS isotherm plot of amorphous apremilast prepared by this method with a weight gain of about 1.64% from about 0% and about 80% RH. Based on the DVS data ( Figures 26A and 26B), Table 1 and according to the Hygroscopicity Definitions described in Example 1, the amorphous apremilast is classified as "slightly hygroscopic".
• Figures 27-30 show a characteristic XRPD profile of the scaled up amorphous form of apremilast stored under the different testing conditions for one week, two weeks, four weeks and three months (panels A-E, respectively).
• Apremilast was stable for three months under all testing conditions (25°C closed, 25°C/60 RH, and 40°C closed) except at 40°C/75 RH.
• the color of the apremilast powder was changed from light yellow to darkened yellow at 40°C/75 RH at the third month, while no change was seen for other conditions and time points (Table 3).
• Figures 31-34 illustrate a characteristic mDSC profile of the scaled up amorphous form of apremilast obtained and stored under the conditions described herein.
• the first glass transition temperature of the amorphous form (77.7°C) did not change significantly at all testing conditions including also at the end of the third month. This is compared to the second glass transition temperature (133.6°C) which changed irregularly and even disappeared at different testing conditions at the first week and second week.
• 40°C/75 RH in the third month This may be related to the melting point of the crystalline form. Further support to this result is in a small spike at 13.5 degrees two theta [2 ⁇ °] observed in the XRPD of 40°C/75 RH measured after three months ( Figure 30, panel E, circled). For other time points of 40°C/75 RH such spike was not detected on XRPD. No heat of fusion peak related to crystalline conversion of the samples stored at 25 °C (closed), 40°C (closed) and 25°C/60 RH for three months was observed.
• the amorphous apremilast obtained by addition of water to acetone precipitation method was scaled up with 81.8% yield.
• the residual acetone and/or water showed about 0.44% based on TGA-MS measurement.
• the amorphous apremilast could be classified as slightly hygroscopic (1.64% weight gain from 0% to 80% RH) based on DVS isotherm analysis. It has good physical stability under different testing conditions (25 °C closed,

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